Summary: One of the major outcomes of the recent sequencing of the Mycobacterium tuberculosis (Mtb) genome was the identification of the multigene families designated PE_PGRS and PE. Since little is known about the expression or function of these genes, we have used the gene Rv1818c (PE_PGRS) and its amino-terminal PE region, as prototypes of the PE_PGRS and PE families, to investigate the immunological response to these proteins during experimental tuberculosis. Following an aerosol challenge of mice with virulent Mtb, a significant humoral immune response was mounted against the purified recombinant PE_PGRS, indicating that these proteins are expressed during TB infection. In animal protection studies, a DNA vaccine encoding the PE region only, generated a significant reduction in the number of viable bacilli in mouse tissues and reduced the lung pathology following aerosol challenge with Mtb, while the PE_PGRS encoding plasmid did not generate an effective immunity. The PE vaccine only elicited a potent T cell response while the PEPGRS vaccine elicited a humoral response. These studies suggest that the PGRS domain when linked to the PE region alters antigen presentation. Ongoing studies are directed towards determining how the PGRS domain of this protein regulates protein stability and antigen presentation and if these effects are observed both in cis and in trans. A collaboration with Johns Hopkins University is testing the efficacy of the PE vaccine in the Rabbit model for TB. Additional studies have provided evidence that PEPGRS proteins are cell surface constituents that have a role in Mtb infection of macrophages and in bacterial-bacterial interactions. Future projects will focus on the characterization of PE proteins and functional properties of the PEPGRS proteins.